Nephronophthisis (NPHP), an autosomal recessive cystic kidney disease, constitutes the most frequent genetic cause for end-stage renal disease (ESRD) in children and young adults. NPHP is a progressive hereditary kidney disease marked by anemia, polyuria, renal loss of sodium, progressing to chronic renal failure, tubular atrophy, interstitial fibrosis, glomerular sclerosis, and medullary cysts.
The most prominent histologic feature of NPHP consists of renal fibrosis, which in chronic renal failure, regardless of origin, represents the pathogenic event correlated most strongly to loss of renal function (Zeisberg et al., Hypertens. 10:315 (2001)). Therefore, NPHP has been considered a model disease for the development of renal fibrosis. The only treatment for NPHP is renal replacement therapy for survival (Smith et al., Am. J. Dis. Child. 69:369 (1945); Fanconi et al., Helv. Paediatr. Acta. 6:1 (1951); Hildebrandt, (1999) Juvenile nephronophthisis. In: Avner E, Holliday M, Barrat T (eds.) Pediatric Nephrology. Williams & Wilkins, Baltimore).
Three distinct gene loci for nephronophthisis, NPHP1 (MIM 256100), NPHP2 (MIM602088), and NPHP3 (MIM 604387), have been mapped to chromosomes 2q13 (Antignac et al., Nature Genet. 3:342 (1993); Hildebrandt et al., Am J Hum Genet 53:1256-1261 (1993)), 9q22 (Haider et al., Am J Hum Genet 63:1404-1410 (1998), and 3q22 (Omran et al., Am J Hum Genet 66:118-127 (2000)), respectively. These disease variants share renal histology of interstitial infiltrations, renal tubular cell atrophy with cyst development, and renal interstitial fibrosis (Waldherr et al., Virchows Arch A Pathol Anat Histol 394:235-254 (1982)). The variants can be distinguished clinically by age of onset at ESRD. Renal failure develops at median ages of 1 year, 13 years, and 19 years, in NPHP2, NPHP1, and NPHP3, respectively (Omran et al., (2000), supra).
Senior-Loken syndrome (SLSN) NPHP is associated with retinal degeneration. Joubert syndrome (JBTS) NPHP is associated with retinal degeneration, cerebellar vermis aplasia, and mental retardation (See, e.g., Saraiva and Baraitser, Am J Med Genet 43, 726-731 (1992)). it was an object of the present invention to further
Clearly there is a great need for characterization of the poorly understood molecular basis of nephronophthisis and its association with retinal degeneration and cerebellar vermis aplasia in Joubert syndrome, as well as for improved diagnostics and treatments for NPHP.